Dr. Michael Davidson from the University of Chicago Medical Center moderated the topic "The Role of CETP Modulation and Inhibition in the Progression of Coronary Heart Disease." with Drs. Christie Ballantyne from the Baylor College of Medicine, Stephen Nicholls from the Cleveland Clinic, and Robert S. Rosenson from the Mount Sinai Hospital Medical Center.

The discussion focused primarily on:

(1) how CETP inhibitors/modulators modify HDL cholesterol levels;

(2) the role of CETP inhibitors in dyslipidemia;

(3) CETP modulation compared to inhibition;

(4) HDL particle concentration compared to HDL cholesterol;

(5) why did torcetrapib increase cardiovascular and total mortality;

(6) newer CETP inhibitors in development and how they differ from torcetrapib

DR. DAVIDSON: Cholesteryl ester transfer protein (CETP) has been a target for the management of risk for cardiovascular disease. This effort began a number of years ago when it was noted that this protein transfers cholesteryl ester in exchange for triglyceride from different lipoproteins, specifically apolipoprotein (apo)B-lipoproteins to high-density lipoproteins (HDL). It’s an exchange that provides equilibrium between the concentration gradients between the different lipoproteins. It also significantly modulates our levels of what we consider HDL and low-density lipoprotein (LDL) cholesterol.

Animals who lack CETP have very high HDL levels and very low LDL levels. Interestingly, human deficiencies of CETP are similar to other mammals who do not have CETP, in other words, they have very high HDL levels and very low LDL levels. There is evidence that inhibiting CETP would raise HDL levels and lower LDL levels and that this is associated with reduction of atherosclerosis in animal models.

Based on these findings, CETP became an intriguing target for the inhibition of atherosclerosis and led to the clinical development of the first CETP-inhibitor, torcetrapib. We’ll discuss torcetrapib in detail in regards to that specific molecule for inhibiting CETP, but I think we’re all aware that the use of this drug was shown to result in increased mortality and was stopped from clinical development in Phase III.

To set the stage, we have new CETP inhibitors in development that do not potentially share the adverse off-target effects of torcetrapib. These new therapies that affect CETP function may have an important therapeutic role in the reduction of atherosclerosis progression. I’m joined today by three experts in this field. Dr. Steve Nicholls, from the Cleveland Clinic; Dr. Christie Ballantyne from the Baylor College of Medicine; and Dr. Robert Rosenson from the Mount Sinai Medical Center in New York City. we will put into clinical context the issues that we wrestle with and hopefully come up with some ideas. These might help us interpret the ongoing clinical trials that will be completing over the next couple of years, and that will determine whether CETP inhibition does in fact represent an important therapy for reducing cardiovascular disease events.

Let me start with you, Bob. What are CETP modulators or inhibitors and how do they work to modify HDL-C levels?

DR. ROSENSON: CETP mediates the transfer of core lipid between lipoproteins, such that the cholesterol cargo in HDL particles is exchanged for the core triglyceride in very low- density lipoprotein (VLDL) particles and core cholesterol in LDL particles. CETP also facilitates the remodeling of plasma HDL particles by converting α HDL to pre-β HDL and transferring cholesteryl ester among HDL sub particles in a process called HDL remodeling. This remodelling of HDL is an important aspect in reverse cholesterol transport and the removal of excess cholesterol from tissue and delivery to the liver.1 The CETP reaction results in reduced cholesterol content in HDL particles and thus smaller HDL particles, which are filtered through the glomerulus and excreted in the urine. Through CETP inhibition, this lipid transfer is blocked resulting in larger cholesterol-containing HDL particles. The heterotypic agents, CETP inhibitors that block cholesterol transfer between lipoprotein classes, increase the cholesterol content of LDL particles, and a conformational change in apoB that facilitates LDL receptor mediated hepatic clearance of larger versus smaller LDL-C particles. This results in reduction in LDL and increases in HDL-C. CETP modulators like dalcetrapib modulate CETP activity by increasing HDL-C while maintaining HDL function. Dalcetrapib also reduces the transfer of cholesterol ester towards apoB containing lipoproteins.2 More importantly dalcetrapib maintains the CETP mediated exchange between HDL (HDL remodeling).

DR. DAVIDSON: Christie, can you give us some kind of background about how CETP inhibitors might work in the treatment of dyslipidemia?

DR. BALLANTYNE: Well, the hope is that we know that there is a very strong epidemiological association between levels of HDL-C and atherosclerosis and coronary events. The higher the level, the fewer coronary events. There are some genetic polymorphisms in the gene that encodes for CETP where people have a slight reduction in CETP activity, they have an increase in HDL-C and they have fewer cardiovascular events. The hope is that these inhibitors will have a beneficial effect on the process of atherosclerosis development and progression and that they would also significantly reduce atherothrombotic cardiovascular events.

DR. DAVIDSON: Bob, please explain the differences between an inhibitor and a modulator and also the differences between the two CETP therapies that are in development right now, anacetrapib and dalcetrapib?

DR. ROSENSON: The two CETP inhibitors that have entered Phase III clinical trials differ dramatically with regard to the effects on lipids and lipoproteins. Agents such as torcetrapib and anacetrapib can be categorized as heterotypic CETP inhibitors or agents that work on lipid exchange between the various lipoprotein classes.

Through the effects of CETP inhibition with a heterotypic CETP inhibitor, there is a reduction in VLDL triglyceride and cholesterol, LDL-C, and an increase in HDL-C. In contrast, dalcetrapib is a CETP modulator that can increase HDL-C while still preserving the CETP mediated exchange between HDL particles.

Although this agent has a negligible effect on reducing LDL particles, it expands the pool of HDL particles by 10% and the cholesterol content in those particles by about 34%.3 In contrast, the heterotypic CETP inhibitor torcetrapib more effectively increases HDL-C but it is less effective than dalcetrapib in increasing HDL particle concentration. Thus, HDL quantity changes differently with homotypic as compared to heterotypic CETP inhibtors. From this perspective, CETP inhibitors cannot be categorized simply in the same group even though they “inhibit” CETP. This is why I prefer this term heterotypic CETP inhibitor and homotypic CETP inhibitor that was initially advanced by Niesor and colleagues.

DR. DAVIDSON: Bob, you said something important. Dalcetrapib increases HDL particle number and torcetrapib does not. What do you think that means as far as potential effects on cardiovascular risk?

DR. ROSENSON: Observational studies and secondary analysis of clinical trials have shown that HDL particle concentration is a more robust predictor of cardiovascular events than is HDL-C. For reasons of analytical simplicity, we focus on the cholesterol cargo in the HDL particles, e.g., the HDL-C concentration, but the total number of HDL particles appear to be more important in human biology.

From Glomset’s initial hypothesis for reverse cholesterol transport in 1964, there has been a focus on HDL-C as a surrogate marker for efflux of cholesterol from the tissues before disposition in the feces. We know that these large cholesterol-containing HDL particles formed from the lecithin:cholesterol acyl transferase reaction have been considered a biomarker of efficient reverse cholesterol transport, but macrophage cholesterol efflux represents only one aspect of the functionality of HDL. For example, small cholesterol depleted HDL particles bind the antioxidant protein paraoxanse with greater affinity than large HDL particles. These small particles have been shown by John Chapman and Anatol Kontush to be more important in mediating the antioxidant and anti-inflammatory effects of HDL particles.

Again, by focusing on HDL-C or the large HDL particles, we may overlook the contributions that small or cholesterol-depleted HDL particles have in mitigating the risk. This may be one of the reasons that a measure of the total HDL particle concentration appears to be a better predictor of cardiovascular events. The total HDL particle concentration accounts for all the various HDL sub-classes involved in its anti-atherothrombotic properties.

DR. DAVIDSON: Torcetrapib was the the first CETP inhibitor in development and Dr. Nicholls was involved with an imaging trial with torcetrapib called ILLUSTRATE.4 What did torcetrapib show in the three imaging trials—RADIANCE 1,5 RADIANCE 2,6 and ILLUSTRATE4? Is there anything that we can take out of those trials that can help us mechanistically regarding torcetrapib? Question number two is, what do we know about torcetrapib now that we didn’t know then that lets us believe it was an off-target effect that may have caused increased cardiovascular and total mortality?

DR. NICHOLLS: We’ve now used arterial wall imaging in a number of clinical trials over the last 20 years to look at the effects of various medical therapies. Many of us had considerable hope that torcetrapib, a drug that had the ability to raise HDL-C well in excess of 50% to 60%, in addition to lowering LDL-C 20% to 25% on top of a statin, should have a fairly profound anti-atherosclerotic effect. In fact, one could postulate that the effect that one would want to see is really disease regression.

We knew that if you treat patients with a statin you get their LDL down to about 80 mg/dL, you could pretty much arrest disease progression. In the clinical development program for torcetrapib in parallel to a very large outcome study were three imaging studies. There was one that looked at coronary atherosclerosis using intravascular ultrasound we performed at the Cleveland Clinic called ILLUSTRATE. There were two studies performed in Europe, one was called RADIANCE 1; one was called RADIANCE 2. They both used serial measures of carotid intima-media thickness, and one of those studies was performed in a cohort with familial hypercholesterolemia; the other in patients with atherogenic dyslipidemic phenotype high triglycerides, low HDL. What was really striking was the complete lack of any effect on disease burden in all three of the studies.

There was no regression at all in lesions, and in fact, the use of this medication didn’t have an impact in slowing disease progression. So in fact, when you look at the results of those studies, which had finished just before we pulled the plug on the outcome study due to the mortality problems, it really gave you an interesting snapshot of what torcetrapib was doing. We have a large outcome study showing us that there is clearly no cardiovascular benefit, in fact, there is this adverse impact on mortality, cardiovascular, and non-cardiovascular events. The drug really just wasn’t doing what we had anticipated that it would do.

I think in some ways the imaging studies at least complemented the information. We then scratched our heads, and we debated for a long time, and, while many of us had thought that inhibiting CETP would be a good thing for the reasons that Bob and Christie have outlined, there were many who still weren’t sure. One could argue that if you inhibit CETP too much that you were going to generate “dysfunctional” HDL. You’d make the HDL particles so full of cholesterol they’d become engorged and they would no longer promote cholesterol efflux. Was that fundamentally a potential problem?

"Cholesteryl ester transfer protein has been an important target for the management of risk for cardiovascular disease. It began a number of years ago when it was noted that this protein transfers cholesteryl ester in exchange for triglyceride from different lipoproteins specifically, apoB-lipoproteins to HDL lipoproteins."~ Michael Davidson, MD

"We certainly have seen a very strong epidemiological association between levels of HDL-C and atherosclerosis and coronary events."~ Christie Ballantyne, MD

"If you keep in mind that the cardiovascular field in general has had numerous examples of therapeutic classes where the first drug failed. In fact, the very first statin failed. It is really important for us to be able to elucidate what happened with torcetrapib so that we can get this path moving forward."~ Stephen Nicholls, MD

"By focusing on HDL-Cor the large HDL particles, we may overlook the contributions that small or cholesterol-depleted HDL particles have in mitigating the risk. This may be one of the reasons that a measure of the total HDL particle concentration appears to be a better predictor of cardiovascular events."~ Robert S. Rosenson, MD